The proposed research program combines three research topics: 1) development and application of methods for efficient asymmetric synthesis using readily available chiral lithium amides as recoverable stereodirecting reagents, 2) total synthesis of complex bioactive molecules, and 3) investigating effects of Cyclic Imine (CI) toxins on various aspects cholinergic transmission by defining their interaction with nicotinic acetylcholine receptors (nAChRs). Total synthesis of complex natural products, in particular CI toxins, has served as a unifying platform for our diverse research interests. Within the first two areas, we will extend the utility of chiral lithium reagents for asymmetric alkylation reactions wih dianionic intermediates. This methodology forms the basis of synthesis strategies directed at the enantioselective preparation of dragmacidin D and a several members of C30-sesquiterpenoid Nuphar thioalkaloids that display an array of biological activity associated with the inhibition of NFkB-regulated pathways. In the third area, we bring in our expertise in scalable synthesis of CI toxins to produce subtype-selective probes and radiotracers for the study of nAChRs. CI toxins are an emerging group of marine toxins with global distribution and unknown human health risks. We will carry out comprehensive functional studies on the interaction of CI toxins with selected subtypes of individual nAChRs using electrophysiology, radioligand-displacement, and other functional studies. Using radiolabeled CI toxins produced by total synthesis, we will investigate in vivo biodistribution of these marine toxins and their effect of developmental biology using chick embryo as a model. In this sense, synthetic CI toxins will serve as unique tools that promise to enrich our knowledge of this important class of ionotropic receptors, including, in long term, additional insight into metabolic turnover and broader impact of nAChRs on neurodegenerative disorders.

Public Health Relevance

Complex molecules derived from nature continue to be important lead compounds for drug development in many therapeutic areas, especially in cancer, infectious diseases, and neurological disorders. Our goals are the development of methods and strategies to enable rapid and economical access to such compounds. Another specific goal is to use a novel class of marine toxins as probes to study the biology associated with nicotinic acetylcholine receptors and their effect on cholinergic signal transmission, which i implicated in a number of physiologically important processes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM077379-07
Application #
8725678
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2008-06-10
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Santa Barbara
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Santa Barbara
State
CA
Country
United States
Zip Code
93106
Alvarado, Joseph; Fournier, Jeremy; Zakarian, Armen (2016) Synthesis of Functionalized Dihydrobenzofurans by Direct Aryl C-O Bond Formation under Mild Conditions. Angew Chem Int Ed Engl 55:11625-8
Kobayashi, Hiroyuki; Eickhoff, John A; Zakarian, Armen (2015) Synthesis of 2-Aminoazoles from Thioesters via α-Heterosubstituted Ketones by Copper-Mediated Cross-Coupling. J Org Chem 80:9989-99
Lu, Ping; Herrmann, Aaron T; Zakarian, Armen (2015) Toward the Synthesis of Nuphar Sesquiterpene Thioalkaloids: Stereodivergent Rhodium-Catalyzed Synthesis of the Thiolane Subunit. J Org Chem 80:7581-9
Jackson, Jeffrey J; Kobayashi, Hiroyuki; Steffens, Sophia D et al. (2015) 10-Step Asymmetric Total Synthesis and Stereochemical Elucidation of (+)-Dragmacidin D. Angew Chem Int Ed Engl 54:9971-5
Stivala, Craig E; Benoit, Evelyne; Aráoz, Rómulo et al. (2015) Synthesis and biology of cyclic imine toxins, an emerging class of potent, globally distributed marine toxins. Nat Prod Rep 32:411-35
Lu, Ping; Jackson, Jeffrey J; Eickhoff, John A et al. (2015) Direct enantioselective conjugate addition of carboxylic acids with chiral lithium amides as traceless auxiliaries. J Am Chem Soc 137:656-9
Bourne, Yves; Sulzenbacher, Gerlind; Radić, Zoran et al. (2015) Marine Macrocyclic Imines, Pinnatoxins A and G: Structural Determinants and Functional Properties to Distinguish Neuronal α7 from Muscle α1(2)βγδ nAChRs. Structure 23:1106-15
Lu, Ping; Mailyan, Artur; Gu, Zhenhua et al. (2014) Enantioselective synthesis of (-)-maoecrystal V by enantiodetermining C-H functionalization. J Am Chem Soc 136:17738-49
Ma, Yun; Stivala, Craig E; Wright, Ashley M et al. (2013) Enediolate-dilithium amide mixed aggregates in the enantioselective alkylation of arylacetic acids: structural studies and a stereochemical model. J Am Chem Soc 135:16853-64
Lu, Ping; Gu, Zhenhua; Zakarian, Armen (2013) Total synthesis of maoecrystal V: early-stage C-H functionalization and lactone assembly by radical cyclization. J Am Chem Soc 135:14552-5

Showing the most recent 10 out of 28 publications